The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses.
Journal: 2016/March - Molecular Cancer
ISSN: 1476-4598
Abstract:
Infection with Human papillomaviruses (HPVs) leads to the development of a wide-range of cancers, accounting for 5% of all human cancers. A prominent example is cervical cancer, one of the leading causes of cancer death in women worldwide. It has been well established that tumor development and progression induced by HPV infection is driven by the sustained expression of two oncogenes E6 and E7. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways that may be equally important for transformation. Among these pathways, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling cascade plays a very important role in HPV-induced carcinogenesis by acting through multiple cellular and molecular events. In this review, we summarize the frequent amplification of PI3K/Akt/mTOR signals in HPV-induced cancers and discuss how HPV oncogenes E6/E7/E5 activate the PI3K/Akt/mTOR signalling pathway to modulate tumor initiation and progression and affect patient outcome. Improvement of our understanding of the mechanism by which the PI3K/Akt/mTOR signalling pathway contributes to the immortalization and carcinogenesis of HPV-transduced cells will assist in devising novel strategies for preventing and treating HPV-induced cancers.
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Molecular Cancer. Dec/31/2014; 14
Published online Apr/16/2015

The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses

Abstract

Introduction

Human papillomaviruses (HPVs) are non-enveloped, epitheliotropic, circular double-stranded DNA viruses [1,2]. HPV infection leads to many different cancers [1,3-5]. It has been well established that high-risk sexually transmitted HPVs such as HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 may lead to the development of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), and anal intraepithelial neoplasia and squamous cell carcinoma (AIN) while cutaneous β-HPVs such as HPV 2, 4, 5, 8, 10 and 15 are suspected to have an etiologic role in skin warts and cancers [3,6-8]. In total, an estimated 5% of human cancers are caused by HPV infections [9].

Genomic instability is a hallmark of carcinogenesis and recognised as an important factor in the accumulation of mutated genes required for carcinogenesis [10]. Endogenous mutations and accumulation of mutational events are very important in the pathogenesis of premalignant lesions and tumour progression, which promote genomic instability to decrease the ability of maintaining the fidelity of DNA sequences [3,11,12]. Published studies have shown that HPV infection causes genomic instability (chromosomal gain or loss) and gene alterations including endogenous mutations and increased DNA damage which are associated with cancer development [13,14]. In HPV-positive cervical and vulva squamous cell carcinomas, the most common lesions were the loss of 11q and gains of 3q, the latter has been found in more than 25% of high grade CIN [13]. A more comprehensive understanding of genomic instability and mutational events associated with the development of cancers caused by HPV infection is needed and will be separately discussed.

It has been well established that HPV E6 and E7 oncogenes inactivate two tumor suppressors (p53 and pRb) in virus-infected cells. Molecular and cell biology approaches have revealed that alterations of additional signalling pathways are equally important for transformation of HPV oncogene-transduced cells [15]. It is now widely accepted that PI3K/Akt/mTOR signalling pathway plays a pivotal role in many human cancers. HPV infection accompanied by E6/E7 expression activates this signalling pathway by altering multiple cellular and molecular events to drive carcinogenesis [16-18]. The PI3K pathway is unique, in that all of the major components of this pathway have been found to be frequently amplified or mutated in HPV-induced cancers [19-24]. The PI3K/Akt/mTOR signalling pathway mediates the multiple cellular and molecular functions through the altered expression of its targeted genes, which are critical to tumor initiation, progression and outcomes [25,26]. Thus, this pathway has been proposed as a promising therapeutic target for many cancers including cervical cancer [27]. In this review, we summarise the current knowledge of the roles of the PI3K/Akt/mTOR signalling pathway in HPV-induced cancers.

HPV life cycle and ATM /p38MAPK/MK2 pathways

HPVs whether they are low-risk and high-risk are epitheliotropic. Infection with two HPVs may be latent or active [28]. The latent HPV infection will complete the viral life cycle to produce virus progeny, which arises via the distinctly different mechanisms from those involved in active HPV infection [29]. During the HPV life cycle, genome amplification is necessary for production of the virus progeny that is prevented until the levels of viral replication proteins rise, and depends on the co-expression of several viral proteins [30]. Expression of E6 and E7 in the lower epithelial layers drives cells into S-phase creates an environment that is conducive for viral genome replication and cell proliferation [31,32]. The lower epithelial layers where HPVs can establish their infection are the only compartment to contain the cells progressing through the cell cycle [33]. Viral capsid proteins (L1 and L2) are expressed to assemble the virus progeny in cells upon their differentiation that also express E4 to complete its life cycle when the infected cell enters the upper epithelial layers [29]. We have confirmed that expression of HPV6b and BPV1 L1 proteins is dependent on cell differentiation in primary keratinocyte culture systems [34-37]. Thus, the late phase of HPV life cycle is closely linked to the differentiation state of the stratified epithelium it infects, with progeny virus only made in the terminally differentiating suprabasal compartment [38].

It has been established that the cellular DNA damage response (DDR) is activated during the HPV life cycle [39]. This activation leads to the induction of an Ataxia-telangiectasia mutation (ATM)-dependent signalling cascade, DNA repair and cell cycle arrest during G2/M to avoid further DNA damage [15,30,34,38,40-42]. Thus, G1, S, G2, and early M phase cell cycle inhibitors efficiently prevented the virus infection [33]. The ATM pathway is responsible for the DDR to double-strand DNA breaks, which is mediated through the action of downstream kinases, such as CHK2 [39,42,43]. The E1 gene might play a key role in this process, which causes double-strand DNA breaks in the host genome [40,44]. By activating the ATM pathway, HPV recruits cellular DNA repair and recombination factors into its replication centers during the stable and vegetative phases of its life cycle [45]. In cells with impaired p53 activity, DNA damage repair requires the activation of p38MAPK along with MAPKAP kinase 2 (MK2) [43]. In HPV-positive cells, phosphorylation of p38 and MK2 proteins was induced along with relocalization to the cytoplasm. Treatment with MK2 or p38 inhibitors blocked HPV genome amplification, confirming the p38/MK2 pathway as a key regulator of the HPV life cycle [43]. Thus, it appears to be clear that the ATM/p38MAPK/MK2 pathways are required for HPVs to complete normal life cycle in the host body.

HPV infection, carcinogensis and PI3K/Akt/mTOR signalling pathway

Active HPV infection which is also known as abortive infection leads to induction of cancer including benign and malignant neoplasms [46]. In the case of carcinogenesis, viral infection induces the initiation and development of cervical and other cancers via their interactions with different cellular signalling pathways in host cells [47]. In addition to the inhibition of p53 and pRb, HPVs also interact with four major upstream pathways (growth factor receptor, notch receptor, Ras and PI3KCA genes) to stimulate host cell survival and proliferation, leading to carcinogenesis through activation and alteration of the components of the PI3K/Akt/mTOR pathway [19,48-53] (Figure 1).

Figure 1
HPVs infect host epithelial cells (keratinocytes) by interacting with different cell surface receptors such as integrin and heparan sulfate proteoglycans (HSPGs). The HPVs replicate themselves using the host cell replication apparatus to express E6/E7/E5 oncoproteins to immortalize the infected cells not only by inhibiting tumour suppressors p53 and Rb and decreasing apoptosis, but also importantly by activating the PI3K/Akt/mTOR signalling pathway. All these processes enhance cell proliferation leading to the carcinogenesis. Solid line: stimulatory influence; Dashed line: inhibitory influence; ⊗: defective process.

PI3K

PI3K modulates different signals to prevent apoptosis and promote cellular survival and proliferation in a wide variety of cell types [54,55]. It has been shown that PI3K is amplified and activated in HPV-induced cervical cancers and other cancers [56]. For instance, PI3K activity is significantly increased in laryngeal papilloma (a hyperplastic tumor of the respiratory tract induced by HPV 6/11), leading to upregulation of EGFR and subsequently activation of MAPK/ERK [57,58]. The activation of MAPK/ERK in turn alters transcription of multiple genes that are important for cell cycle regulation and cell proliferation. Furthermore, HPV infection causes laryngeal epithelial cells to develop recurrent respiratory papillomas where expression of keratin-13 (K13), a cell differentiation marker of human mucosal keratinocytes, is diminished [58]. This is due to the increased PI3K activity that enhances papillomas cell proliferation and represses terminal differentiation (and hence the failure to upregulate K13 expression) [58].

Liu et al. reported that BPV-1 L1 and L2 pre-mRNAs are spliced in keratinocytes, which contain two exonic splicing enhancers [59]. Each exonic splicing enhancer has an alternative splicing factor (ASF) and splicing factor 2 (SF2), which together play an important role in viral RNA expression and splicing at the proximal 3′ splice site [59]. Depletion of ASF/SF2 from the cells greatly decreases viral RNA expression and RNA splicing at the proximal 3′ splice site. Activation-rescued viral RNA expression and splicing in ASF/SF2-depleted cells are mediated through the PI3K/Akt pathway and associated with the enhanced expression of other serine/arginine-rich (SR) proteins [59]. The ASF/SF2 co-operate with H-Ras to enhance cellular proliferation and protect cells from apoptosis by upregulating expression of phosphorylated SR proteins (SRp30s and SRp40) through the PI3K/Akt pathway in cervical and other cancers [59,60]. A published study has also reported that HPV infection-induced IL-17 expression can stimulate Mcl-1 expression to promote lung tumor cell progression through the PI3K pathway [61].

Akt

Akt is a serine/threonine-specific protein kinase, which plays a key role in multiple cellular processes including apoptosis and cell proliferation. Phosphorylation and activation of Akt also play an important role in the majority of HPV-caused malignancies including anal squamous cell carcinomas (ASCCs) [7]. Sixty six percent (82/125) of ASCCs show cellular accumulation of p-Akt associated with nuclear accumulation of MDM2 [7]. Thirty nine out of 46 formalin-fixed cervical neoplastic specimens showed p-Akt on serine 473 [62]. Forty-eight percent (12/25) of cervical cancer patients at stage Ib2-IIb exhibited Akt activation in cancer cells [63]. The radiation sensitivity of HPV-infected H&N cancers also correlates to Akt activation [64]. Mechanistically, HPV infection causes genome instability due to integration of the viral DNA into the host genome. Thus, mutations of PIK3CA gene (which encodes PI3K) in HPV-infected cells and tissues or HPV-DNA transformants may account for Akt activation present in cervical and other types of HPV-induced cancers, since PIK3CA shows the highest frequency of gain-of-function mutations in these cancers [20,63,65]. Oncogenic mutations and amplification of PIK3CA activate PI3K/Akt signalings to drive the HPV-induced tumorigenesis [19,21,65].

Akt phosphorylation is required for a BRCT (BRCA1 carboxyl-terminal) domain-containing protein TopBP1 to interact with other transcription factors, especially E2F1. E2F1 functions as a tumor suppressor to induce apoptosis [66,67]. Phosphorylated Akt (p-Akt) interacts with E2F1 to repress its proapoptotic activity and induce oligomerization of TopBP1 [66]. Furthermore, an endosomal/lysosomal cysteine protease cathepsin L (Ctsl) has been reported to act as an anti-tumor protease. Ctsl is critical for termination of growth factor signalling in the endosomal/lysosomal compartment of keratinocytes and has an inhibitory role in Akt activation in HPV-induced carcinogenesis [68,69]. Therefore, activation of Akt/MAPK pathway is only upregulated in Ctsl-deficient cells [68]. Additionally, papillomavirus-binding factor (PBF), a transcriptional regulator, controls the promoter activity of HPVs by binding to the regulatory sequences of certain papillomavirus types and Huntington’s disease binding protein 2 (HDBP2) through the 14-3-3β protein via two motifs (RSRSLSFSEP and LSKSAP) [70,71]. Activated Akt phosphorylates the two motifs, allowing PBF to associate with 14-3-3β to promote cell survival and growth [70]. These studies suggest that activation of Akt may contribute to the HPV-induced tumorigenesis. It has been reported that high levels of p-Akt might be an unfavourable prognostic marker for relapse-free survival in oropharyngeal cancer [51].

Mammalian genomes contain three Akt genes, Akt1, Akt2 and Akt3. Akt1 encodes the principal Akt isoform that regulates apoptosis [72]. HPVs may differentially affect epithelial Akt activity, as the three Akt isoforms behave differently during epidermal tumorigenesis [73,74] . Cutaneous HPV8 early genes reduce epidermal Akt activity primarily due to down-regulation of Akt1. In contrast, Akt activity can be focally stimulated by up-regulation and phosphorylation of Akt2 in both papillomas and HPV gene-induced epidermal tumours. In SCC, Akt1 is commonly down-regulated consistent with a viral influence, whereas Akt2 up-regulation is widespread. Activation of upregulated Akt2 by serine phosphorylation associates with high-grade tumours, and is characteristic of SCC associated with malignancy [74]. Interestingly, high level of Akt2 is often associated with the presence of β-HPV species (HPV 15) and the up-regulation of p16INK4a and Akt/PI3K pathways [51]. p-Akt2 is over-expressed in basal cell carcinoma (BCC) accompanied by up-regulation of tumor suppressor p16INK4a [51,75]. Overexpression of p16INK4a is common in cervical cancer where pRb protein is inactivated by high-risk HPVs. However, it is still unclear whether p16INK4a overexpression can be used as an indicator of pathogenic activity of high-risk HPVs. Nevertheless, the PI3K/ Akt /mTOR pathway is associated with the up-regulation of p16INK4a by HPVs [19,65,75-79]. So far, it remains unclear whether and how Akt 3 plays a functional role in HPV-induced tumorigenesis.

mTOR

mTOR kinase acts as a cellular rheostat that integrates the signals from a variety of cellular signalling pathways to sense growth factor, nutrient availability and energy status. Recently, it has been reported that activation of Akt /mTOR can be detected within several minutes following exposure of human keratinocytes to HPV16 pseudovirions [80]. mTOR activation is frequently observed in cervical squamous cell carcinoma, most HPV(+) head and neck squamous cell carcinomas (HNSCC), HPV(+) oropharyngeal cancers (OPSCC), cervical cancer squamous cell carcinomas (CCSCC) lesions and cell lines [2,17,63,81]. A tissue microarray analysis has shown that 13 cervical cancer patients (52%) express phosphorylated mTOR (p-mTOR) in the cytoplasm and membrane of cancer cells [63]. Both p-mTOR expression and distant metastasis significantly correlate with the response to nucleus accumbens core [63]. Another analysis of 20 samples each of normal cervix, high-grade squamous intraepithelial lesions (HSIL) and invasive SCCs, derived from a total of 60 cases of cervical biopsies and cervical conizations, has revealed an increased nuclear translocation of both p-mTOR(Ser2448) and p70S6K(Thr389), indicating the constitutive activation and overexpression of the mTOR pathway in HSIL and SCC [82]. All the studies show that mTOR activation occurs in at least 60% of the HPV-caused cancer patients, consistent with the Akt activation data discussed above, suggesting that mTOR activation may play an important role in most of the HPV-induced carcinogenesis.

mTOR is a crucial metabolic sensor in the growth factor receptor (GFR) pathway, which integrates growth factor signals in cells. The increased nuclear translocation of p-mTOR(Ser2448) and p70S6K(Thr389) correlates with overexpression of the upstream signal transducer EGFR, increased cell cycles and mitotic indices [82]. The activated PI3K/ Akt /mTOR signalling pathway induces phosphorylation of the mTOR complex 1 substrates ,4E-BP1 and S6K, which leads to induction of the functional protein translational machinery and inhibition of autophagy at the early stages of virus-host cell interaction [80]. All these events are partially dependent upon activation of EGFR. Preclinical studies have shown that both the mTOR inhibitor (rapamycin) and EGFR-tyrosine kinase inhibitor (erlotinib) can induce growth delay of xenografted HPV-containing cervical carcinoma cells [83].

A high level of p-mTOR can serve as an independent prognostic marker to predict poor response to chemotherapy and survival of cervical cancer patients [63]. Concurrent use of mTOR inhibitors such as rapamycin and RAD001 and standard-of-care cisplatin/radiation therapy (CRT) has been applied in HPV(+) HNSCC and CCSCC tumour xenografts and mouse models for evaluating the preclinical efficacy of mTOR inhibition [77,84]. Both inhibitors effectively decrease mTOR activity, leading to a remarkable decrease in tumor burden [77] and prolonged survival in immunocompromised mice [84]. It has also been reported that treatment with PI3K inhibitors combined with NaBT significantly decreases the viability of cervical cancer HeLa cells. Inhibition of PI3K enhances NaBT-mediated apoptosis through activation of caspase 3 and caspase 9 and the cleavage of poly (ADP-ribose) polymerase (PARP) [85]. Taken together, these studies provide a rationale for the clinical application of PI3K/mTOR inhibitors as a molecular targeted approach for treating HPV-associated cancers.

HPV oncogene-mediated PI3K/Akt/mTOR signalling pathway

Recently, several review papers have provided comprehensive summaries of the biological and biochemical activities of three HPV oncoproteins: E6, E7 and E5 [86-88]. Here, we focus on discussing the oncogenic activities of HPV E6, E7 and E5 proteins in inducing the PI3K/Akt/mTOR signalling pathway (Figure 1). Human keratinocytes, a special type of epithelial cells that have a finite life span and do not undergo spontaneous immortalization, are the host cells of HPV infection, [89]. Following HPV infection, the keratinocytes are immortalized and transformed by the viral oncogenes (E6/E7) that act on multiple cellular events including inhibition of p53 and pRb [90-92], altered expression of multiple genes (approximately 4% of the genes on the array) [26] and activation of several signalling pathways, especially, the PI3K/Akt/mTOR signalling pathway [89,93-95]. The PI3K/Akt/mTOR pathway may in turn mediate multiple cellular functions necessary for HPV-induced carcinogenesis (Figure 1) [96-98].

E6 oncogene

HPV E6 oncoproteins are the key players in HPV-induced cancers. The E6 oncoproteins from high-risk mucosotrophic HPVs (α-HPVs) target not only P53, but also a range of host-cell proteins for proteasome-mediated degradation, resulting in alteration of multiple cellular and molecular events [99-101]. A genome-wide analysis has shown that E6 up-regulates many genes at the transcript level associated with cancer hallmarks including cell cycle, migration, PI3K/Akt /mTOR signalling to mediate cellular transformation [102]. The high-risk HPV E6 oncoproteins contain a PDZ-binding domain; a common structural domain of 80–90 amino acids found in the signalling proteins of multiple organisms [103]. The PDZ-binding domain plays a key role in HPV-mediated cellular transformation. Through this domain, the E6 targets a member of the group of PDZ domain-containing molecules that are mediated by the PI3K/Akt signals [98,102,104]. For example, HPV 16/18 E6 proteins promote proteasome-mediated degradation of human disc large (hDlg) tumor suppressor protein by binding to the second PDZ domain of the hDlg through their C-terminal xS/TxV/L (where x represents any amino acid, S/T serine or threonine, and V/L valine or leucine) motif [2,105]. High-risk HPV E6 oncoproteins efficiently degrade members of the PDZ domain-containing membrane-associated guanylate kinase (MAGUK) family and a PDZ protein, Na (+)/H (+) exchange regulatory factor 1 (NHERF-1) [103]. E6 degrades MAGUK by binding to it with inverted domain structure 1 (MAGI-1), which is one of the most strongly bound PDZ domain-containing substrates of E6. E6 interacts with MAGI-1 to facilitate the perturbation of tight junctions. Restoration of MAGI-1 expression in HPV positive tumour cells induces cell growth arrest and apoptosis [106].

HPV E6 variants (E6*) can act as an adaptor molecule linking a ubiquitin ligase to target proteins, which contain class 1 PDZ domains and are involved in cell junction stability and signalling [100]. E6* proteins differentially modulate hDlg degradation to rebound the levels of activated PTEN and Akt and strongly enhance expression of p-PI3K contributing to activate MAPKs and promote cell proliferation [2,102]. High-risk HPV E6 can target certain substrates both directly and indirectly through the E6* proteins and the two E6 proteins may cooperate in their degradation [100]. In the absence of full-length HPV-18 E6, HPV-18 E6* expression also downregulates the expression levels of Akt, Dlg, and Scribble [100]. It has also been reported that HPV16 E6 and HPV18 E6* oncoproteins activate MAPK signalling pathway to promote cell proliferation by upregulating p-PI3K [102,107]. HPV18 intra-type variations may result in differential abilities to activate cell-signalling molecules such as Akt and MAPKs, directly involved in cell survival and proliferation [102]. Functional studies confirm that HPV18 E6 from an African variant has a major effect on the cellular processes including cell cycle and migration [108]. A specific E6 (amino acid 83) (E6aa83V) variant is also linked to invasive tumours. The E6aa83V variant activates PI3K signalling pathway and strengthens the possibility of the existence of Ras-independent mechanisms to recreate signalling through classical Ras effector pathways [107]. The variant also enhances MAPK signalling and cooperative transformation with deregulated Notch1 signalling. These studies suggest that intra-type genome variations of high risk HPVs may differ in their abilities to mediate Akt /MAPKs signalling, thus presenting a differential threat to the development of cervical and other cancers.

E6 proteins of three HPVs (HPV1, 8 and 16), and BPV1 interact with acidic LxxLL motifs of transcriptional coregulator MAML1 to target many host proteins such as the mammalian target of rapamycin complex 1 (mTORC1) to delay keratinocyte differentiation [109-111]. The interaction of HPV-8 E6 with MAML1 causes delay of keratinocyte differentiation [111]. According to the crystal structure analysis, both BPV1 and HPV16 E6 proteins contain two zinc-finger domains and a linker helix [109,110]. Both E6 proteins can bind to LxxLL motifs of the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively to form a basic-hydrophobic pocket. The basic-hydrophobic pocket captures the helical LxxLL motifs to stimulate mTORC1 signalling, and cap-dependent translation, through activation of the PDK1 and mTORC2 kinases leading to genetic alterations [109,110]. Such genetic alterations include intra-type genome variations of the virus and changes in chromatin proteins and histone modifications in host cells during HPV16-induced carcinogenesis [107]. The integrity of LxxLL and PDZ protein binding domains is important for activation of cap-dependent translation by high-risk mucosal HPV E6 proteins [109,110].

Generally, β-HPV E6 proteins interact with fewer cellular proteins as is also observed for the α-HPV E6 [58]. This is because β-HPVs such as HPV5 and HPV8 E6 proteins lack the domains for binding to the LxxLL and PDZ motifs. An exception is that both α- and β-HPV E6 proteins can directly interact with p300 protein, a transcriptional co-activator. The interaction appears to be much stronger with β-HPV 5/8 E6 than with α-HPV 16 E6 or β-HPV 38 E6 [58]. Enhanced interaction between β-HPV 5/8 E6 and p300 leads to p300 degradation and the blockage of Akt/p300 association in a proteasomal-dependent but E6AP-independent manner [58]. Decreased p300 concomitantly affects downstream signalling events including expression of differentiation markers K1/10 and involucrin. These results reveal a unique way in which β-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the α-HPVs. Furthermore, HPV16 E6 degrade tuberin, the product of mTOR inhibitor tuberous sclerosis complex 2 (e.g., tumour suppressor gene TSC2), by binding to the DILG motif and ELVG motif located in the carboxyl-terminal of Tuberin, which leads to the phosphorylation of p70 S6 kinase (S6K) [112-114]. The E6 binding domain interacting with tuberin is different to that of p53 [113]. The S6K phosphorylation is tightly associated with HPV16 infection in cervical and oesophageal cancers [112]. Immunohistochemical analysis of p-S6K(Thr389) and p-S6(Ser235/236) in 140 cervical cancer and 161 oesophageal cancer specimens has revealed that both p-S6K and p-S6 were detected significantly more frequently in the HPV16-infected cervical cancer specimens than those in the HPV16-negative specimens [112]. HPV16 E6 activates S6K via Akt signalling, which promotes S6K phosphorylation and sustains the activity of the mTORC1 and mTORC2 signalling cascade [112,115]. Alternatively, HPV16 E6 increases the mTORC1 activity through enhanced phosphorylation of mTOR and activation of the downstream signalling through S6K and eukaryotic initiation factor binding protein 1 (4E-BP1) [116]. HPV16 E6 also causes Akt activation through the upstream kinases PDK1 and mTORC2 under conditions of nutrient deprivation. HPV16 E6 increases protein synthesis by enhancing translation initiation complex assembly at the 5′ mRNA cap. The increase in cap-dependent translation likely results from HPV16 E6-induced Akt /mTORC1 activation, as the assembly of the translation initiation complex and cap-dependent translation are rapamycin sensitive. HPV16 E6-mediated activation of mTORC1 signalling and cap-dependent translation may be a mechanism employed by HPV to promote viral replication in HPV oncoprotein-expressing proliferating cells under conditions of limited nutrient supply [116].

NHERF-1 is a molecular pathway organizer that plays an important role in a number of cellular processes including signal transduction, cellular transformation and recruitment of membrane, cytoplasmic, and cytoskeletal signalling proteins into functional complexes [117]. HPV16 E6 mediated-NHERF-1 degradation correlates with the activation of the PI3K/Akt pathway during carcinogenesis [103]. HPV16 E7 plays a concerted role in E6 mediated NHERF1 degradation [103]. E7 activates the cyclin-dependent kinase complexes to promote the accumulation of a phosphorylated form of NHERF-1 that is preferentially targeted by E6. However, HPV18 E6 does not degrade NHERF-1, suggesting that HPV E6-induced NHERF-1 degradation is HPV type-dependent [103]. In addition, E6-upregulated cIAP2 protein confers resistance to cisplatin in HPV 16/18-infected lung cancer through EGFR/PI3K/Akt pathway [118]. Thus, EGFR or PI3K inhibitor combined with cisplatin may improve the chemotherapeutic efficacy in HPV-induced cancers [118].

E7 oncogene

HPV E7 protein is responsible for pRb disruption in HPV-induced carcinogenesis. E7 binds to and inactivates pRb to disturb the normal cell division process, allowing the cells to grow out of control and unhindered and thus become cancerous. Clinically, decreased Rb expression is consistently associated with increased CIN grade in the HPV-infected woman’s cervices. It has been reported that HPV E7 significantly up-regulates Akt activity in differentiated keratinocytes, which depends on the ability of E7 binding to and inactivating the proteins of pRb family [17] . Up-regulation of AKT activity and loss of pRb were observed in HPV-positive cervical high-grade squamous intraepithelial lesions when compared with normal cervical tissue. Therefore, pRb expression is inversely correlated with Akt activity in HPV-positive cervical high-grade squamous intraepithelial lesions [17]. E7 directly activates Akt by phosphorylating it at two key sites (threonine 308 and serine 473), which subsequently leads to phosphorylation of BAD, a downstream target of Akt [16]. Akt phosphorylation is associated with activated Notch1 signalling that regulates the PI3K pathway [27,49]. It has been reported that protein phosphatase 2 (PP2 or PP2A), a ubiquitous and conserved serine/threonine phosphatase, interacts with the 35 kDa catalytic and 65 kDa structural subunits of p-Akt to dephosphorylate Akt [119]. Akt dephosphorylation results in loss of its activity in preventing cell apoptosis. HPV E7 binds to the two PP2A subunits to prevent their interactions with p-Akt, thereby maintaining Akt signal activation [16].

Through the PI3K/Akt signalling pathway, HPV E7 oncoprotein inhibits the functions of two cyclin-dependent kinase inhibitors, p21Cip1 and p27Kip1 [120,121]. As a tumour suppressor, p21Cip1 binds to the cyclin E/CDK2 complex to maintain Rb in a phosphorylated state [76]. In the absence of immortalizing oncogenes or genetic lesions, activation of the Raf/Ras pathway results in a p21Cip1-dependent cell cycle arrest [122]. In contrast, in the E7-transformed human primary cells, E7 cooperates with Ras to abolish the p21Cip1-mediated growth arrest [121]. E7 bypasses Raf-induced arrest and alleviates inhibition of cyclin E-CDK2 without suppressing Raf-specific synthesis of p21Cip1 or derepressing p21Cip1-associated CDK2 complexes by sustaining Akt activity [2,123,124]. P27Kip1 is a marker of poor prognosis in several forms of cancer when localized to the cytoplasm and has been implicated as a positive regulator of cellular motility [120]. HPV 16 E7 protein can modulate the cytoplasmic localization of p27Kip1 and may in turn regulate tumor metastasis/aggressiveness through the PI3K/ Akt pathway [120]. E7 also antagonizes the ability of p27Kip1 to block cyclin E-associated kinase and to inhibit transcription of cyclin A in vitro [125].

Apoptosis as a normal process of cellular self-destruction or suicide is one of the major contributors to the development of a normal immune system, which serves a protective role in our bodies. In response to oncogenic insults, normal human cells execute a defence response that culminates in apoptosis [126]. In HPV infection, expression of E6/E7 oncogens induces cellular immortalization and transformation and carcinogenesis through the immune evasion or resistance against apoptosis and adaptive immune surveillance. Several studies have reported that activation of Akt induced by HPV E7 expression plays a crucial role in immune resistance [126-128]. Due to HPV16 E7 expression, activation of Akt in TC-1/PO and A17 tumours induces an immune resistance against apoptotic cell death [127]. The E7-induced activation of Akt in A17 tumor cells also contributes to significantly upregulate expression of the key antiapoptotic proteins including Bcl-2, Bcl-xL, phosporylated Bad (p-Bad), Bcl-w, cIAP-2 and surviving [127]. Treatment of A17 tumor cells with the Akt inhibitor, API-2, reduces the expression of the antiapoptotic proteins markedly leading to an increase in the apoptosis of tumor cells [128]. It has also been reported that overexpression of E6/E7 from the high-risk HPV16 significantly upregulates expression of cellular inhibitor of apoptosis protein 2 (c-IAP2), which is necessary for the E6/E7-induced resistance to apoptosis and cell survival in HPV16 E6/E7-immortalized human oral keratinocytes [128]. Akt inhibitors markedly abrogate the antiapoptotic effect of c-IAP2 and some other antiapoptotic proteins on different cancer cells [129,130].

Furthermore, normal human diploid fibroblasts expressing the HPV16 E7 oncoprotein are predisposed to apoptosis when they are deprived of growth factors such as IGF-1 in serum-starved medium [126]. The apoptosis of serum-starved HPV16 E7-expressing cells is directly associated with low phosphorylation of Akt and highly activated caspase 3 that plays a central role in the execution-phase of cell apoptosis. Exogenously added IGF-1 can partially inhibit the cell death response associated with upregulated p-Akt in serum-starved E7-expressing cells [126]. In support of these previous findings, we observed that HPV16 E7 inhibits IFN-γ-mediated MHC class I antigen presentation and CTL-induced lysis through blocking interferon regulatory factor-1 (IRF-1) expression in mouse keratinocytes [131]. IRF-1 is a tumor suppressor that can regulate gene expression involved in induction of apoptosis and cell growth control by reducing p-Akt expression [132]. Thus, the activation of PI3K/Akt pathway induced by HPV E6/E7 oncogenes may represent a new mechanism of immune escape and have important implications for developing a novel strategy in cancer immunotherapy against immune-resistant tumor cells [127,128].

As mentioned above, keratinocytes are the host cells of HPV infection. In normal epithelial tissues, cell division and proliferation of keratinocytes are confined to the basal layer, where mitogenic signals are balanced by survival signals transmitted through PI3K/Akt pathway [133]. Once in the suprabasal layer, keratinocytes stop dividing and enter a differentiation program. Primary keratinocytes in in vitro cultures resemble in vivo epidermal development when they enter a differentiation program [134]. We and others have previously observed that both human and mouse primary keratinocytes grown in vitro proceed to cell differentiation with downregulation of proliferation markers including K14 and K5 and upregulation of differentiation markers such as involucrin and K10 [36,135,136]. However, expression of HPV 16 E7 in human foreskin keratinocytes in in vitro cultures induces phosphorylation of AKT on threonine 308 and serine 473 to significantly inhibit cell differentiation and cause hyperproliferation [16,17]. It has been reported that a dual epidermal growth factor receptor (EGFR) and HER2 inhibitor Lapatinib reduces expression of E6/E7 and Akt phosphorylation to prevent cell proliferation and induce cell death in HPV-positive cell lines [137]. The HPV E7-activated Akt also enhances keratinocyte migration through downregulation of RhoA activity [120]. Either treatment of PI3K or AKT inhibitors or PIK3CA siRNA transfection results in a significant decrease of E7 expression and E7-induced Akt phosphorylation, consequently, leading to that cellular viability and migration are dramatically reduced in HPV16-transfected keratinocytes [65]. The HPV E7-activated Akt regulates not only tumourigenesis and invasion [138], but also tumor metastasis/aggressiveness by modulating the cytoplasmic localization of p27 [120].

E5 oncogene

HPV E5 gene encodes an 83-amino acid, membrane-bound protein, which plays an important role in early cervical carcinogenesis by regulating several cellular pathways [139-141]. HPV16 E5 itself cannot immortalize human or mouse primary cells, but can enhance the immortalization of keratinocytes by E6/E7[142] and potentiate the transforming activity of E7 in murine fibroblasts and activation of EGFR in human keratinocytes that naturally express high levels of EGFR after EGF stimulation [104,143-146].

HPV16 E5 induces the anchorage-independent growth of murine fibroblasts by overexpressing EGFR [147]. HPV16 E5 also induces expression of VEGF, which plays a central role in switching on angiogenesis during early cervical carcinogenesis through activation of EGFR and phosphorylation of Akt and ERK1/2 [148,149]. Thus, HPV 16 E5 may activate the EGFR/PI3K/Akt/MEK/ERK1/2 pathway. Recently, it has been reported that expression of HPV16 E5 in undifferentiated keratinocytes alters the key paracrine mediator of epithelial homeostasis, keratinocyte growth factor receptor (KGFR/FGFR2b) [146]. KGFR down-modulation, together with a ligand-dependent decrease of p63, is responsible for a E5-mediated decrease of the early differentiation marker K1 and impairment of keratinocyte differentiation [146].

HPV E5 may act as a survival factor as the E5-expressing cells in human keratinocyte culture exhibit a significant reduction in UVB-irradiation induced apoptosis [145]. A genome-wide microarray assay reveals that E5 expression significantly alters expression of 179 genes including upregulation of PI3K and PKCδ and downregulation of lamin A/C protein, which lead to inhibition of apoptosis and the establishment of persistent infection in the epithelium [150]. The E5-mediated protection against apoptosis can be blocked by two specific inhibitors of the PI3K/MAPK pathways (wortmannin and PD98059), suggesting that the PI3K/MAPK pathways are involved in the protection from apoptosis by HPV16 E5 [145]. Inhibition of the PI3K/Akt signalling prevents the down-regulation of KGFR/p63, supporting an oncogenic role of E5 through the PI3K/Akt pathway [146]. In addition, two BPV1 E5 mutants are severely defective for focus formation, but still competent for enhanced growth through the PI3K/Akt/cyclin D3 pathway together with a Grb2-Gab1-SHP2 complex and JNK protein [151,152]. Thus, it appears that HPV E5 oncoprotein can directly or indirectly target several other substrates to regulate the PI3K/Akt /mTOR pathway.

HPV pseudovirions and PI3K/Akt /mTOR signals

It is well documented that induction and progression of tumours by HPV infection are driven by the continuing expression of E6 and E7 oncogenes that degrade and inactivate p53 and pRb, respectively [122,153]. However, two studies have reported that HPV pseudovirions and virus-like particles (VLPs, or as pseudovirions), which do not contain E6/E7 genes or their protein products, also can activate PI3K signalling in human keratinocytes and epidermoid carcinoma cells through the signals of growth factor receptor (GFR) [80] and α6β4 integrin receptor [154]. The pseudovirions-induced PI3K activity results in efficient activation of its two down streamers Akt and mTOR and subsequent phosphorylation of the mTOR complex 1 substrates 4E-BP1 and S6K [80] and of FKHR and GSK3β (Figure 2) [154]. These events combined with activation of Ras/MAPK to enhance cell proliferation and inhibit autophagy [80,154].

Figure 2

HPV pseudovirions enter the host epithelial cells (keratinocytes) by interacting with α6β4 integrin receptor [154] or growth factor receptor [80] to enhance cell proliferation through the activation of the PI3K/Akt/mTOR and PI3k signalling pathway. Without the oncogenic roles of E6/E7E5, it is impossible for HPV pseudovirions to induce formation of cancerous cells by activating the PI3K/Akt signalling pathway.

Generally, it is impossible that attachment of HPV pseudovirions and other viruses to the surface of cells activates the PI3K/Akt signalling pathway leading to the development of cancerous cells. However, several other published studies appear to suggest that PI3K signalling pathway plays a critical role in cellular entry of pseudovirions of HPV [155] and other viruses such as Zaire Ebola virus (ZEBOV) [156], SV 40 [157] and Epstein–Barr virus (EBV) [158]. Infection with either radiation-inactivated ZEBOV virus or SV40 VLPs activates PI3K/Akt by expression of phosphorylated PI3K/Akt in the infected cells [157,158]. On the other hand, inhibition of PI3K significantly reduces infection rate of HPV 16 pseudovirions (50–60% reduction) [155] and ZEBOV VLPs [156]. In addition, EBV latent membrane protein 2A can transform the EBV-infected cells to become cancerous through constitutive activation of the PI3K/Akt/Ras/MAPK pathway [158]. Nontheless, whether the PI3K/Akt pathway can play a role in HPV-induced carcinogenesis independent of E6/E7 proteins remains questioned. Thus, more detailed studies are required to improve our current understanding of the full spectrum of mechanisms underlying HPV-induced carcinogenesis.

Concluding remarks

Recently, the PI3K/Akt/mTOR pathway has been identified as an important signalling pathway to tightly modulate many cellular events including the physiological activities of mitogenic or oncogenic factors, leading to the genesis of many human cancers. Published studies have shown that expression of HPV E6/E7 oncoproteins induces HPV transformed cells to be cancerous not only causing degradation and destabilization of p53 and pRb, but also altering multiple cellular and molecular events through activation of the PI3K/Akt/mTOR signalling pathway. The PI3K/Akt/mTOR signalling pathway in HPV-infected cells is activated through both mutation of the pathway components and activation of upstream signalling molecules. Activation of this pathway contributes to genetic instability, deregulation of proliferation, resistance to apoptosis, and changes in metabolism characteristics, eventually leading to the malignant transformation of the infected cells. This signalling pathway may potentially represents both a great therapeutic opportunity and a practical challenge for treating HPV-induced cancers. Thus, further understanding of the molecular mechanisms by which HPV infection activates the PI3K/Akt/mTOR signalling pathway and the biological roles of this pathway in HPV-induced carcinogenesis will improve the disease prevention, patient care, and surveillance strategies for HPV-positive cancers. We suggest that one important research direction will be to devise the novel biomarker-driven therapeutic strategies to target the PI3K/Akt/mTOR pathway in HPV-associated cancers with a specific molecular profile and evaluate the efficacy of the potential therapeutic agents.

Footnotes

Lifang Zhang and Jianhong Wu contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

KNZ first suggested to write up a review paper of the role of the PI3K signals in human cancers induced by HPV infection. JW and LZ searched for the published studies. LZ, JW, MTL, LZ and KNZ discussed the topic and wrote up the paper. All authors read and approved the final manuscript.

Authors’ information

Lifang Zhang and Jianhong Wu are joint first author.

Acknowledgement

Research work in HPV biology and immunolgy at LZ’s laboratory was supported in part by grants from the National Natural Science Foundation of China (81172463 to LZ). Research work in MTL and KNZ laboratories was partially supported by the Australian National Health and Medical Research Council (to MTL and KNZ) and by Cancer Council of Queensland, Australia (to KNZ). We thank Professor Marin Lavin and Dr Lambro Johnson for correcting the grammar mistakes and reading the revised manuscript.

Abbreviations

ASCCsAnal squamous cell carcinomasAINAnal intraepithelial neoplasiaASF/SF2Alternative splicing factor/splicing factor 2BCDDButyl 2-cyano-3, 11-dioxours-1,12-dien-24-oateCDKCyclin-dependent kinaseCINCervical intraepithelial neoplasia4E-BP1Eukaryotic initiation factor binding protein 1EGFREpithelial growth factor receptorERK1/2Extracellular signal-regulated kinase-1/2FAKFocal adhesion kinaseGFRGrowth factor receptorGSK3βGlycogen synthase kinase-3 betaHCCHuman cervical carcinoma tissueshDlgHuman disc largeHFKsHuman foreskin keratinocytesHIF-1αHypoxia-inducible factor-1alphaHMECsHuman mammary epithelial cellsHPVHuman papillomavirusHRHigh-riskHSILHigh grade cervical squamous intraepithelial lesionIGF-1Insulin-like growth factor 1JNKc-Jun N-terminal kinaseKCC1KC1 co-transport-1MAPKMitogen-activated protein kinaseMAGUKMembrane-associated guanylate kinasemTORMammalian target of rapamycinc-iNOSInducible nitric oxide synthasesNHERF-1Na(+)/H(+) exchange regulatory factor 1PI3KPhosphatidylinositol 3-kinasesPINPenile intraepithelial neoplasiaPTENPhosphatase and tensin homologRbRetinoblastomaS6KS6 kinaseSCCSquamous cell carcinomaSDF-1Stromal Derived Factor-1SEK-1Extracellular signal-regulated kinase 1Skp2S phase kinase-associated protein 2SOS-1Son of seven less homolog 1TSC2Tuberous sclerosis complex 2VEGFVascular endothelial growth factorVINVular intraepithelial neoplasiaVLPsVirus-like particles

References

  • 1. ZhaoKNChenJCodon usage roles in human papillomavirusRev Med Virol2011216397411[PubMed][Google Scholar]
  • 2. GardiolDKuhneCGlaunsingerBLeeSSJavierRBanksLOncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradationOncogene19991840548796[PubMed][Google Scholar]
  • 3. zur HausenHViruses in human cancersScience19912545035116773[PubMed][Google Scholar]
  • 4. TaloraCCialfiSSegattoOMorroneSKimCJFratiLConstitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathwaysExp Cell Res2005305234354[PubMed][Google Scholar]
  • 5. AuvinenECrusiusKSteuerBAlonsoAHuman papillomavirus type 16 E5 protein (review)Int J Oncol19971161297304[PubMed][Google Scholar]
  • 6. SmolaSHuman papillomaviruses and skin cancerAdv Exp Med Biol2014810192207[PubMed][Google Scholar]
  • 7. PatelHPolanco-EcheverryGSegditsasSVolikosEMcCartALaiCActivation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinomaInt J Cancer200712112266873[PubMed][Google Scholar]
  • 8. TaloraCCialfiSOlivieroCPalermoRPascucciMFratiLCross talk among Notch3, pre-TCR, and Tal1 in T-cell development and leukemogenesisBlood20061078331320[PubMed][Google Scholar]
  • 9. SchillerJTLowyDRUnderstanding and learning from the success of prophylactic human papillomavirus vaccinesNat Rev Microbiol2012101068192[PubMed][Google Scholar]
  • 10. NegriniSGorgoulisVGHalazonetisTDGenomic instability–an evolving hallmark of cancerNat Rev Mol Cell Biol20101132208[PubMed][Google Scholar]
  • 11. Zur HausenHPapillomaviruses and cancer: from basic studies to clinical applicationNat Rev Cancer20022534250[PubMed][Google Scholar]
  • 12. DuensingSMüngerKMechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteinsInt J Cancer2004109215762[PubMed][Google Scholar]
  • 14. OjesinaAILichtensteinLFreemanSSPedamalluCSImaz-RosshandlerIPughTJLandscape of genomic alterations in cervical carcinomasNature201450674883715[PubMed][Google Scholar]
  • 15. MoodyCALaiminsLAHuman papillomavirus oncoproteins: pathways to transformationNat Rev Cancer201010855060[PubMed][Google Scholar]
  • 16. PimDMassimiPDilworthSMBanksLActivation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2AOncogene2005245378308[PubMed][Google Scholar]
  • 17. MengesCWBagliaLALapointRMcCanceDJHuman papillomavirus type 16 E7 up-regulates AKT activity through the retinoblastoma proteinCancer Res2006661155559[PubMed][Google Scholar]
  • 18. TinkerAVEllardSWelchSMoensFAlloGTsaoMSPhase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199)Gynecol Oncol2013130226974[PubMed][Google Scholar]
  • 20. MaYYWeiSJLinYCLungJCChangTCWhang-PengJPIK3CA as an oncogene in cervical cancerOncogene20001923273944[PubMed][Google Scholar]
  • 21. BertelsenBISteineSJSandveiRMolvenALaerumODMolecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylationInt J Cancer20061188187783[PubMed][Google Scholar]
  • 22. ChioseaSIGrandisJRLuiVWDiergaardeBMaxwellJHFerrisRLPIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinomaBMC Cancer201313602[PubMed][Google Scholar]
  • 23. LuiVWHedbergMLLiHVangaraBSPendletonKZengYFrequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkersCancer Discov2013377619[PubMed][Google Scholar]
  • 24. ThomasSMSahuBRapireddySBahalRWheelerSEProcopioEMAntitumor effects of EGFR antisense guanidine-based peptide nucleic acids in cancer modelsACS Chem Biol20138234552[PubMed][Google Scholar]
  • 25. McAuliffePFMeric-BernstamFMillsGBGonzalez-AnguloAMDeciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesisClin Breast Cancer201010Suppl 3S5965[PubMed][Google Scholar]
  • 26. NeesMGeogheganJMHymanTFrankSMillerLWoodworthCDPapillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kappaB-responsive genes in cervical keratinocytesJ Virol2001759428396[PubMed][Google Scholar]
  • 27. WuJChenCZhaoKNPhosphatidylinositol 3-kinase signaling as a therapeutic target for cervical cancerCurr Cancer Drug Targets201313214356[PubMed][Google Scholar]
  • 28. StubenrauchFLaiminsLAHuman papillomavirus life cycle: active and latent phasesSemin Cancer Biol19999637986[PubMed][Google Scholar]
  • 29. MaglennonGADoorbarJThe biology of papillomavirus latencyOpen Virol J201261907[PubMed][Google Scholar]
  • 30. MoodyCALaiminsLAHuman papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiationPLoS Pathog2009510[PubMed][Google Scholar]
  • 31. DoorbarJPapillomavirus life cycle organization and biomarker selectionDis Markers2007234297313[PubMed][Google Scholar]
  • 32. OhSTLongworthMSLaiminsLARoles of the E6 and E7 proteins in the life cycle of low-risk human papillomavirus type 11J Virol200478526206[PubMed][Google Scholar]
  • 33. PyeonDPearceSMLankSMAhlquistPLambertPFEstablishment of human papillomavirus infection requires cell cycle progressionPLoS Pathog200952[PubMed][Google Scholar]
  • 34. DingJDoorbarJLiBZhouFGuWZhaoLExpression of papillomavirus L1 proteins regulated by authentic gene codon usage is favoured in G2/M-like cells in differentiating keratinocytesVirology201039914658[PubMed][Google Scholar]
  • 35. FangNXGuWDingJSaundersNAFrazerIHZhaoKNCalcium enhances mouse keratinocyte differentiation in vitro to differentially regulate expression of papillomavirus authentic and codon modified L1 genesVirology2007365118797[PubMed][Google Scholar]
  • 36. ZhaoKNGuWFangNXSaundersNAFrazerIHGene codon composition determines differentiation-dependent expression of a viral capsid gene in keratinocytes in vitro and in vivoMol Cell Biol20052519864355[PubMed][Google Scholar]
  • 37. GuWDingJWangXde KluyverRLSaundersNAFrazerIHGeneralized substitution of isoencoding codons shortens the duration of papillomavirus L1 protein expression in transiently gene-transfected keratinocytes due to cell differentiationNucleic Acids Res20073514482032[PubMed][Google Scholar]
  • 38. LongworthMSLaiminsLAPathogenesis of human papillomaviruses in differentiating epitheliaMicrobiol Mol Biol Rev200468236272[PubMed][Google Scholar]
  • 39. ReinsonTTootsMKadajaMPipitchRAllikMUstavEEngagement of the ATR-dependent DNA damage response at the human papillomavirus 18 replication centers during the initial amplificationJ Virol201387295164[PubMed][Google Scholar]
  • 40. DavyCDoorbarJG2/M cell cycle arrest in the life cycle of virusesVirology2007368221926[PubMed][Google Scholar]
  • 41. HeltAMFunkJOGallowayDAInactivation of both the retinoblastoma tumor suppressor and p21 by the human papillomavirus type 16 E7 oncoprotein is necessary to inhibit cell cycle arrest in human epithelial cellsJ Virol200276201055968[PubMed][Google Scholar]
  • 42. SoutoglouEMisteliTActivation of the cellular DNA damage response in the absence of DNA lesionsScience20083205882150710[PubMed][Google Scholar]
  • 43. SatsukaAMehtaKLaiminsLp38MAPK and MK2 pathways are important for the differentiation-dependent human papillomavirus life cycleJ Virol2015893191924[PubMed][Google Scholar]
  • 44. Fradet-TurcotteAMoodyCLaiminsLAArchambaultJNuclear export of human papillomavirus type 31 E1 is regulated by Cdk2 phosphorylation and required for viral genome maintenanceJ Virol201084221174760[PubMed][Google Scholar]
  • 45. GillespieKAMehtaKPLaiminsLAMoodyCAHuman papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centersJ Virol2012861795206[PubMed][Google Scholar]
  • 46. DoorbarJThe papillomavirus life cycleJ Clin Virol200532Suppl 1S715[PubMed][Google Scholar]
  • 47. BurdEMHuman papillomavirus and cervical cancerClin Microbiol Rev2003161117[PubMed][Google Scholar]
  • 48. LechnerMFramptonGMFentonTFeberAPalmerGJayATargeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumorsGenome Med20135549[PubMed][Google Scholar]
  • 49. WuJChenJZhangLMasciPPZhaoKNFour major factors regulate phosphatidylinositol 3-kinasesignaling pathway in cancers induced by infection of human PapillomavirusesCurr Med Chem20142126305769[PubMed][Google Scholar]
  • 50. PsyrriASeiwertTYJimenoAMolecular pathways in head and neck cancer: EGFR, PI3K, and moreAmerican Society of Clinical Oncology educational book / ASCO American Society of Clinical Oncology Meeting201324655[Google Scholar]
  • 51. WonHSJungCKChunSHKangJHKimYSSunDIDifference in expression of EGFR, pAkt, and PTEN between oropharyngeal and oral cavity squamous cell carcinomaOral Oncol2012481098590[PubMed][Google Scholar]
  • 52. ZhangEFengXLiuFZhangPLiangJTangXRoles of PI3K/Akt and c-Jun signaling pathways in human papillomavirus type 16 oncoprotein-induced HIF-1alpha, VEGF, and IL-8 expression and in vitro angiogenesis in non-small cell lung cancer cellsPLoS One201497[PubMed][Google Scholar]
  • 53. MurakamiSSakurai-YagetaMMaruyamaTMurakamiYTrans-homophilic interaction of CADM1 activates PI3K by forming a complex with MAGuK-family proteins MPP3 and DlgPLoS One201492[PubMed][Google Scholar]
  • 54. YaoRCooperGMRequirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factorScience1995267520620036[PubMed][Google Scholar]
  • 55. Kauffmann-ZehARodriguez-VicianaPUlrichEGilbertCCofferPDownwardJSuppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKBNature199738566165448[PubMed][Google Scholar]
  • 56. LeeCMFuhrmanCBPlanellesVPeltierMRGaffneyDKSoissonAPPhosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell linesClin Cancer Res20061212506[PubMed][Google Scholar]
  • 57. ZhangPSteinbergBMOverexpression of PTEN/MMAC1 and decreased activation of Akt in human papillomavirus-infected laryngeal papillomasCancer Res2000605145762[PubMed][Google Scholar]
  • 58. HowieHLKoopJIWeeseJRobinsonKWipfGKimLBeta-HPV 5 and 8 E6 promote p300 degradation by blocking AKT/p300 associationPLoS Pathog201178[PubMed][Google Scholar]
  • 59. LiuXMayedaATaoMZhengZMExonic splicing enhancer-dependent selection of the bovine papillomavirus type 1 nucleotide 3225 3′ splice site can be rescued in a cell lacking splicing factor ASF/SF2 through activation of the phosphatidylinositol 3-kinase/Akt pathwayJ Virol2003773210515[PubMed][Google Scholar]
  • 60. McFarlaneMGrahamSVHuman papillomavirus regulation of SR proteinsBiochem Soc Trans2010384111621[PubMed][Google Scholar]
  • 61. ChangYHYuCWLaiLCTsaoCHHoKTYangSCUp-regulation of interleukin-17 expression by human papillomavirus type 16 E6 in nonsmall cell lung cancerCancer20101162048009[PubMed][Google Scholar]
  • 62. KohrenhagenNVoelkerHUSchmidtMKappMKrockenbergerMFrambachTExpression of transketolase-like 1 (TKTL1) and p-Akt correlates with the progression of cervical neoplasiaJ Obstet Gynaecol Res2008343293300[PubMed][Google Scholar]
  • 63. FariedLSFariedAKanumaTSanoTNakazatoTTamuraTPredictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapyOncol Rep20061615763[PubMed][Google Scholar]
  • 64. GuptaAKLeeJHWilkeWWQuonHSmithGMaityARadiation response in two HPV-infected head-and-neck cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling through AKTInt J Radiat Oncol Biol Phys200974392833[PubMed][Google Scholar]
  • 65. HenkenFEBanerjeeNSSnijdersPJMeijerCJDe-CastroAJRoslFPIK3CA-mediated PI3-kinase signalling is essential for HPV-induced transformation in vitroMol Cancer20111071[PubMed][Google Scholar]
  • 66. LiuKPaikJCWangBLinFTLinWCRegulation of TopBP1 oligomerization by Akt/PKB for cell survivalEmbo J200625204795807[PubMed][Google Scholar]
  • 67. AokiIHiguchiMGotohYNEDDylation controls the target specificity of E2F1 and apoptosis inductionOncogene20133234395464[PubMed][Google Scholar]
  • 68. DennemarkerJLohmullerTMayerleJTackeMLerchMMCoussensLMDeficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermisOncogene20102911161121[PubMed][Google Scholar]
  • 69. JoyceJABaruchAChehadeKMeyer-MorseNGiraudoETsaiFYCathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesisCancer Cell20045544353[PubMed][Google Scholar]
  • 70. SichtigNSillingSStegerGPapillomavirus binding factor (PBF)-mediated inhibition of cell growth is regulated by 14-3-3betaArch Biochem Biophys20074641909[PubMed][Google Scholar]
  • 71. TsukaharaTNabetaYKawaguchiSIkedaHSatoYShimozawaKIdentification of human autologous cytotoxic T-lymphocyte-defined osteosarcoma gene that encodes a transcriptional regulator, papillomavirus binding factorCancer Res2004641554428[PubMed][Google Scholar]
  • 72. DattaSRBrunetAGreenbergMECellular survival: a play in three AktsGenes Dev19991322290527[PubMed][Google Scholar]
  • 73. SahJFBalasubramanianSEckertRLRorkeEAEpigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinasesJ Biol Chem2004279131275562[PubMed][Google Scholar]
  • 74. O’ShaughnessyRFAkgulBStoreyAPfisterHHarwoodCAByrneCCutaneous human papillomaviruses down-regulate AKT1, whereas AKT2 up-regulation and activation associates with tumorsCancer Res20076717820715[PubMed][Google Scholar]
  • 75. PaoliniFCarboneABenevoloMSilipoVRolloFCovelloRHuman Papillomaviruses, p16INK4a and Akt expression in basal cell carcinomaJ Exp Clin Cancer Res201130108[PubMed][Google Scholar]
  • 76. ShinMKBalsitisSBrakeTLambertPFHuman papillomavirus E7 oncoprotein overrides the tumor suppressor activity of p21Cip1 in cervical carcinogenesisCancer Res20096914565663[PubMed][Google Scholar]
  • 77. MolinoloAAMarshCElDMGanganeNJennisonKHewittSmTOR as a molecular target in HPV-associated oral and cervical squamous carcinomasClin Cancer Res2012189255868[PubMed][Google Scholar]
  • 78. IshikawaMFujiiTMasumotoNSaitoMMukaiMNindlICorrelation of p16INK4A overexpression with human papillomavirus infection in cervical adenocarcinomasInt J Gynecol Pathol200322437885[PubMed][Google Scholar]
  • 79. DimriGBandHBandVMammary epithelial cell transformation: insights from cell culture and mouse modelsBreast Cancer Res2005741719[PubMed][Google Scholar]
  • 80. SurviladzeZSterkRTDeharoSAOzbunMACellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-Kinase/Akt/mTOR pathway and inhibition of autophagyJ Virol2013875250817[PubMed][Google Scholar]
  • 81. SewellABrownBBiktasovaAMillsGBLuYTysonDRReverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancerClin Cancer Res2014209230011[PubMed][Google Scholar]
  • 82. FengWDuanXLiuJXiaoJBrownREMorphoproteomic evidence of constitutively activated and overexpressed mTOR pathway in cervical squamous carcinoma and high grade squamous intraepithelial lesionsInt J Clin Exp Pathol20092324960[PubMed][Google Scholar]
  • 83. SchilderRJSillMWLeeYCMannelRA phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group StudyInt J Gynecol Cancer200919592933[PubMed][Google Scholar]
  • 84. CoppockJDWiekingBGMolinoloAAGutkindJSMiskiminsWKLeeJHImproved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibitionNeoplasia201315662030[PubMed][Google Scholar]
  • 85. ParkJKChoCHRamachandranSShinSJKwonSHKwonSYAugmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3-kinase inhibition in the human cervical cancer cell-lineCancer Res Treat20063821127[PubMed][Google Scholar]
  • 86. DiMaioDPettiLMThe E5 proteinsVirology20134451–299114[PubMed][Google Scholar]
  • 87. RomanAMungerKThe papillomavirus E7 proteinsVirology20134451–213868[PubMed][Google Scholar]
  • 88. Vande PolSBKlingelhutzAJPapillomavirus E6 oncoproteinsVirology20134451–211537[PubMed][Google Scholar]
  • 89. Van DoorslaerKBurkRDEvolution of human papillomavirus carcinogenicityAdv Virus Res2010774162[PubMed][Google Scholar]
  • 90. RomanczukHVillaLLSchlegelRHowleyPMThe viral transcriptional regulatory region upstream of the E6 and E7 genes is a major determinant of the differential immortalization activities of human papillomavirus types 16 and 18J Virol1991655273944[PubMed][Google Scholar]
  • 91. NakamuraTWilliams-SimonsLWestphalHA human papillomavirus type 18 E6/E7 transgene sensitizes mouse lens cells to human wild-type p53-mediated apoptosisOncogene1997142529918[PubMed][Google Scholar]
  • 92. Martinez-CruzABSantosMLaraMFSegrellesCRuizSMoralMSpontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressorsCancer Res200868368392[PubMed][Google Scholar]
  • 93. ZhangSWuXJiangTLuYMaLLiangMThe up-regulation of KCC1 gene expression in cervical cancer cells by IGF-II through the ERK1/2MAPK and PI3K/AKT pathways and its significanceEur J Gynaecol Oncol20093012934[PubMed][Google Scholar]
  • 94. TangXZhangQNishitaniJBrownJShiSLeADOverexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1 alpha protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cellsClin Cancer Res2007139256876[PubMed][Google Scholar]
  • 95. HylandPLMcDadeSSMcCloskeyRDicksonGJArthurKMcCanceDJEvidence for alteration of EZH2, BMI1, and KDM6A and epigenetic reprogramming in human papillomavirus type 16 E6/E7-expressing keratinocytesJ Virol20118521109991006[PubMed][Google Scholar]
  • 96. CrookTMorgensternJPCrawfordLBanksLContinued expression of HPV-16 E7 protein is required for maintenance of the transformed phenotype of cells co-transformed by HPV-16 plus EJ-rasEmbo J1989825139[PubMed][Google Scholar]
  • 97. Cordova-AlarconECentenoFReyes-EsparzaJGarcia-CarrancaAGarridoEEffects of HRAS oncogene on cell cycle progression in a cervical cancer-derived cell lineArch Med Res20053643116[PubMed][Google Scholar]
  • 98. VeeraraghavaluKSubbaiahVKSrivastavaSChakrabartiOSyalRKrishnaSComplementation of human papillomavirus type 16 E6 and E7 by Jagged1-specific Notch1-phosphatidylinositol 3-kinase signaling involves pleiotropic oncogenic functions independent of CBF1;Su(H);Lag-1 activationJ Virol20057912788998[PubMed][Google Scholar]
  • 99. WhelanRDKileySCParkerPJTetradecanoyl phorbol acetate-induced microtubule reorganization is required for sustained mitogen-activated protein kinase activation and morphological differentiation of U937 cellsCell Growth Differ19991042717[PubMed][Google Scholar]
  • 100. PimDTomaicVBanksLThe human papillomavirus (HPV) E6* proteins from high-risk, mucosal HPVs can direct degradation of cellular proteins in the absence of full-length E6 proteinJ Virol20098319986374[PubMed][Google Scholar]
  • 101. LaceMJAnsonJRHaugenTHTurekLPInterferon regulatory factor (IRF)-2 activates the HPV-16 E6-E7 promoter in keratinocytesVirology201039922709[PubMed][Google Scholar]
  • 102. Contreras-ParedesADe la Cruz-HernandezEMartinez-RamirezIDuenas-GonzalezALizanoME6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3-kinase (akt/PI3K) signaling pathwayVirology200938317885[PubMed][Google Scholar]
  • 103. AccardiRRubinoRScaliseMGheitTShahzadNThomasME6 and E7 from human papillomavirus type 16 cooperate to target the PDZ protein Na/H exchange regulatory factor 1J Virol20118516820816[PubMed][Google Scholar]
  • 104. PimDCollinsMBanksLHuman papillomavirus type 16 E5 gene stimulates the transforming activity of the epidermal growth factor receptorOncogene1992712732[PubMed][Google Scholar]
  • 105. KiyonoTHiraiwaAFujitaMHayashiYAkiyamaTIshibashiMBinding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor proteinProc Natl Acad Sci U S A19979421116126[PubMed][Google Scholar]
  • 107. ChakrabartiOVeeraraghavaluKTergaonkarVLiuYAndrophyEJStanleyMAHuman papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by notch signaling and oncogenic RasJ Virol20047811593445[PubMed][Google Scholar]
  • 108. Fragoso-OntiverosVMariaA-GRContreras-ParedesAVaca-PaniaguaFAlonsoHLLopez-CamarilloCGene expression profiles induced by E6 from non-European HPV18 variants reveals a differential activation on cellular processes driving to carcinogenesisVirology201243218190[PubMed][Google Scholar]
  • 109. SpangleJMGhosh-ChoudhuryNMungerKActivation of cap-dependent translation by mucosal human papillomavirus E6 proteins is dependent on the integrity of the LXXLL binding motifJ Virol20128614746672[PubMed][Google Scholar]
  • 110. ZanierKCharbonnierSSidiAOMcEwenAGFerrarioMGPoussin-CourmontagnePStructural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteinsScience201333961206948[PubMed][Google Scholar]
  • 111. BrimerNLyonsCWallbergAEVandePSBCutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signalingOncogene20123143463946[PubMed][Google Scholar]
  • 112. ZhouYPanYZhangSShiXNingTKeYIncreased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancerBr J Cancer200797221822[PubMed][Google Scholar]
  • 113. LuZHuXLiYZhengLZhouYJiangHHuman papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberinJ Biol Chem2004279343566470[PubMed][Google Scholar]
  • 114. ZhengLDingHLuZLiYPanYNingTE3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6Genes Cells200813328594[PubMed][Google Scholar]
  • 115. SpangleJMMungerKThe HPV16 E6 oncoprotein causes prolonged receptor protein tyrosine kinase signaling and enhances internalization of phosphorylated receptor speciesPLoS Pathog201393[PubMed][Google Scholar]
  • 116. SpangleJMMungerKThe human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesisJ Virol201084189398407[PubMed][Google Scholar]
  • 117. CardoneRAGrecoMRCapulliMWeinmanEJBuscoGBellizziANHERF1 acts as a molecular switch to program metastatic behavior and organotropism via its PDZ domainsMol Biol Cell20122311202840[PubMed][Google Scholar]
  • 118. WuHHWuJYChengYWChenCYLeeMCGoanYGcIAP2 upregulated by E6 oncoprotein via epidermal growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway confers resistance to cisplatin in human papillomavirus 16/18-infected lung cancerClin Cancer Res20101621520010[PubMed][Google Scholar]
  • 119. LiLRenCHTahirSARenCThompsonTCCaveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2AMol Cell Biol200323249389404[PubMed][Google Scholar]
  • 120. CharetteSTMcCanceDJThe E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent mannerOncogene20072652738690[PubMed][Google Scholar]
  • 121. ThalerSHahnelPSSchadADammannRSchulerMRASSF1A mediates p21Cip1/Waf1-dependent cell cycle arrest and senescence through modulation of the Raf-MEK-ERK pathway and inhibition of AktCancer Res2009695174857[PubMed][Google Scholar]
  • 122. RorkeEAZhangDChooCKEckertRLJacobbergerJWTGF-beta-mediated cell cycle arrest of HPV16-immortalized human ectocervical cells correlates with decreased E6/E7 mRNA and increased p53 and p21(WAF-1) expressionExp Cell Res2000259114957[PubMed][Google Scholar]
  • 123. WestbrookTFNguyenDXThrashBRMcCanceDJE7 abolishes raf-induced arrest via mislocalization of p21(Cip1)Mol Cell Biol20022220704152[PubMed][Google Scholar]
  • 124. AhnJWonMChoiJHKimYSJungCRImDSReactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21(Cip1) downregulation are required for shikonin-induced apoptosisApoptosis201318787081[PubMed][Google Scholar]
  • 125. Zerfass-ThomeKZwerschkeWMannhardtBTindleRBotzJWJansen-DurrPInactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoproteinOncogene19961311232330[PubMed][Google Scholar]
  • 126. EichtenARudDSGraceMPiboonniyomSOZacnyVMungerKMolecular pathways executing the “trophic sentinel” response in HPV-16 E7-expressing normal human diploid fibroblasts upon growth factor deprivationVirology200431918193[PubMed][Google Scholar]
  • 127. NohKHKangTHKimJHPaiSILinKYHungCFActivation of Akt as a mechanism for tumor immune evasionMol Ther200917343947[PubMed][Google Scholar]
  • 128. YuanHFuFZhuoJWangWNishitaniJAnDSHuman papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosisOncogene20052432506978[PubMed][Google Scholar]
  • 129. MartelliAMTazzariPLTabelliniGBortulRBilliAMManzoliLA new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cellsLeukemia20031791794805[PubMed][Google Scholar]
  • 130. SongLXiongHLiJLiaoWWangLWuJSphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-kappaB pathway in human non-small cell lung cancerClin Cancer Res2011177183949[PubMed][Google Scholar]
  • 132. LeeJHChunTParkSYRhoSBInterferon regulatory factor-1 (IRF-1) regulates VEGF-induced angiogenesis in HUVECsBiochim Biophys Acta200817839165462[PubMed][Google Scholar]
  • 133. BrazilDPHemmingsBATen years of protein kinase B signalling: a hard Akt to followTrends Biochem Sci2001261165764[PubMed][Google Scholar]
  • 134. MarceloCLKimYGKaineJLVoorheesJJStratification, specialization, and proliferation of primary keratinocyte cultures. Evidence of a functioning in vitro epidermal cell systemJ Cell Biol1978792 Pt 135670[PubMed][Google Scholar]
  • 135. JuliandiBAbematsuMNakashimaKEpigenetic regulation in neural stem cell differentiationDev Growth Differ2010526493504[PubMed][Google Scholar]
  • 136. de GiorgiVSestiniSMassiDGhersetichILottiTKeratinocyte growth factor receptorsDermatol Clin200725447785[PubMed][Google Scholar]
  • 137. FumagalliIDugueDBibaultJEClemensonCVozeninMCMondiniMCytotoxic effect of lapatinib is restricted to human papillomavirus-positive head and neck squamous cell carcinoma cell linesOncoTargets Ther2015833545[Google Scholar]
  • 138. CichonACPickardAMcDadeSSSharpeDJMoranMJamesJAAKT in stromal fibroblasts controls invasion of epithelial cellsOncotarget201347110316[PubMed][Google Scholar]
  • 139. KimSHOhJMNoJHBangYJJuhnnYSSongYSInvolvement of NF-kappaB and AP-1 in COX-2 upregulation by human papillomavirus 16 E5 oncoproteinCarcinogenesis20093057537[PubMed][Google Scholar]
  • 140. OhJMKimSHLeeYISeoMKimSYSongYSHuman papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cellsCarcinogenesis20093011419[PubMed][Google Scholar]
  • 141. OhJMKimSHChoEASongYSKimWHJuhnnYSHuman papillomavirus type 16 E5 protein inhibits hydrogen-peroxide-induced apoptosis by stimulating ubiquitin-proteasome-mediated degradation of Bax in human cervical cancer cellsCarcinogenesis201031340210[PubMed][Google Scholar]
  • 142. StoreyAGreenfieldIBanksLPimDCrookTCrawfordLLack of immortalizing activity of a human papillomavirus type 16 variant DNA with a mutation in the E2 gene isolated from normal human cervical keratinocytesOncogene19927345965[PubMed][Google Scholar]
  • 143. RamirezdMASarmentero-EstradaJBelda-IniestaCTaronMRamirezdMVCejasPExpression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective studyLancet Oncol200781088997[PubMed][Google Scholar]
  • 144. SerewkoMMPopaCDahlerALSmithLStruttonGMComanWAlterations in gene expression and activity during squamous cell carcinoma developmentCancer Res20026213375965[PubMed][Google Scholar]
  • 145. ZhangBSpandauDFRomanAE5 protein of human papillomavirus type 16 protects human foreskin keratinocytes from UV B-irradiation-induced apoptosisJ Virol200276122031[PubMed][Google Scholar]
  • 146. PurpuraVBelleudiFCaputoSTorrisiMRHPV16 E5 and KGFR/FGFR2b interplay in differentiating epithelial cellsOncotarget201342192205[PubMed][Google Scholar]
  • 147. CrusiusKKaszkinMKinzelVAlonsoAThe human papillomavirus type 16 E5 protein modulates phospholipase C-gamma-1 activity and phosphatidyl inositol turnover in mouse fibroblastsOncogene1999184867148[PubMed][Google Scholar]
  • 148. KimSHJuhnnYSKangSParkSWSungMWBangYJHuman papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3K/AktCell Mol Life Sci2006637–89308[PubMed][Google Scholar]
  • 149. ElyamanWBassilRBradshawEMOrentWLahoudYZhuBNotch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cellsImmunity201236462334[PubMed][Google Scholar]
  • 150. KiviNGrecoDAuvinenPAuvinenEGenes involved in cell adhesion, cell motility and mitogenic signaling are altered due to HPV 16 E5 protein expressionOncogene20082718253241[PubMed][Google Scholar]
  • 151. BorzacchielloGMogaveroSDeVGRopertoSDellaSLRopertoFActivated platelet-derived growth factor beta receptor expression, PI3K-AKT pathway molecular analysis, and transforming signals in equine sarcoidsVet Pathol200946458997[PubMed][Google Scholar]
  • 152. CorteggioAUrraroCRopertoSRopertoFBorzacchielloGPhosphatidylinositol-3-kinase-AKT pathway, phospho-JUN and phospho-JNK expression in spontaneously arising bovine urinary bladder tumoursJ Comp Pathol20101432–31738[PubMed][Google Scholar]
  • 153. NguyenMMPotterSJGriepAEDeregulated cell cycle control in lens epithelial cells by expression of inhibitors of tumor suppressor functionMech Dev20021121–210113[PubMed][Google Scholar]
  • 154. FothergillTMcMillanNAPapillomavirus virus-like particles activate the PI3-kinase pathway via alpha-6 beta-4 integrin upon bindingVirology2006352231928[PubMed][Google Scholar]
  • 155. SchelhaasMShahBHolzerMBlattmannPKuhlingLDayPMEntry of human papillomavirus type 16 by actin-dependent, clathrin- and lipid raft-independent endocytosisPLoS Pathog201284[PubMed][Google Scholar]
  • 156. SaeedMFKolokoltsovAAFreibergANHolbrookMRDaveyRAPhosphoinositide-3 kinase-Akt pathway controls cellular entry of Ebola virusPLoS Pathog200848[PubMed][Google Scholar]
  • 157. Butin-IsraeliVUziDAbd-El-LatifMPizovGEdenAHavivYSDNA-free recombinant SV40 capsids protect mice from acute renal failure by inducing stress response, survival pathway and apoptotic arrestPLoS One200838[PubMed][Google Scholar]
  • 158. FukudaMLongneckerREpstein-Barr virus latent membrane protein 2A mediates transformation through constitutive activation of the Ras/PI3-K/Akt PathwayJ Virol200781179299306[PubMed][Google Scholar]
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